Prostaglandin I2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I-2, in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1 and pharynx-defective-1 induction. In particular, we found that PGI(2) production increased during the course of AD development. Then, PGI(2) accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1/1 expression. As PGI(2) is an important metabolic by-product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1/1 in neuronal cells and APP/PS1 mice. More importantly, -amyloid protein (A) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1/1, which was blocked by NS398 incubation. Finally, the induction of APH-1/1 was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI(2)-induced AD progression but also are instrumental for improving clinical therapies to combat AD.